This proposal focuses on understanding the mechanisms by which environmental signals are translated into cellular functions in human intestinal epithelial cells (IECs). Previous studies of IEC proliferation have examined regulation by polypeptide growth factors and to a lesser extent, bioactive lipids, but none of the studies were performed in normal human colonic epithelial cells. Specifically, we will focus on the molecular mechanisms of action of the G protein-coupled receptor (GPCR) agonists lysophosphatidic acid (LPA) and bradykinin (BK) in nontransformed human colonic epithelial cells. The central hypothesis we will address is that GPCR agonists stimulate signal transduction pathways that lead to cellular proliferation and production of the proinflammatory and angiogenic chemokine interleukin-8 (IL-8). To test our hypothesis, we will pursue these specific aims and characterize: 1) mitogenic effects and IL-8 production in response to LPA and BK; 2) the role of the ERK pathway in mitogenesis and IL-8 production; and 3) the regulation and role of protein kinase D-2 (PKD-2) in mitogenesis and IL-8 production. By elucidating key signal transduction pathways in intestinal epithelium, we will better understand the mechanisms underlying the processes of normal growth and neoplasia in the GI epithelium. This proposal will provide additional experience in advanced techniques in molecular biology and allow for transition into a new area of investigation, chemokine biology. My immediate priority is to obtain grant support to continue both my research and my development as a scientist. I seek an environment for my initial junior faculty position that will provide me with both a depth of resources to stimulate scientific growth and a strong commitment to protected research time. Therefore, I have chosen UCLA and my Sponsors Drs. Enrique Rozengurt and Robert Strieter for their expertise in signal transduction and chemokine biology, respectively. My long-term goal in academic medicine is to establish an independent program of research in the field of GI signal transduction, while continuing a focused practice of clinical gastroenterology. These efforts, hopefully, will contribute to the advancement of basic research as it relates to health. We believe that findings from this proposal will help advance our understanding of fundamental processes in mucosal repair and hopefully allow for design of new therapeutic strategies for human intestinal diseases.